1. Estrogen (E2) induces proliferation and squamous differentiation of the cervical and vaginal epithelium during the estrous cycle, while progesterone and retinoids maintain the simple columnar epithelium of the endocervix and uterine horns. We have defined the effects of ovariectomy and subsequent estrogen administration on the differentiation of mouse ectocervical epithelium. We have investigated whether retinoid receptors (RARs and RXRs) are responsive to estrogen status during cervical epithelial differentiation induced by a single dose of estrogen in ovariectomized adult mice. Northern blot analysis demonstrated a prolonged induction of RXRalpha and RARgamma gene expression by E2 in the mouse cervix and vagina. The induction of these retinoid receptors suggests that they may be implicated in epithelial growth and differentiation in response to E2. Moreover, potential heterodimeric interactions among these receptors indicates that normal, cyclical epithelial differentiation results from the interplay of these molecules. The induction of RXRalpha and RARgamma by E2, and their expression pattern in relation to ER suggest that they are needed to coordinate specific genetic programs that result in cervical epithelial growth and differentiation. 2. RARalpha protein is reduced in high risk papillomas, relative to low risk papillomas, and the promoting agent mezerein, that induces high risk papillomas, causes a substantial reduction in RARalpha in non- tumorous skin. Transducing cultured normal keratinocytes with v-rasHa reduces RARalpha and gamma proteins in nuclear extracts and decreases RAR mediated transcriptional activity. Introduction of a recombinant RARalpha expression vector into papilloma cells inhibits growth in response to retinoic acid. Modulation of RARs could contribute to the neoplastic phenotype directly or indirectly through interaction with AP-1 and may be involved in the differential promoting activity of mezerein and TPA, thereby influencing the selection of tumors at high risk for malignant conversion.